This revised R21 addresses the role of T-cell responses to cytomegalovirus (CMV) in the pathogenesis of frailty, chronic inflammation, and immune activation in people with and without HIV infection, all of which are key areas of this RFA. Frailty is a syndrome characterized by diminished physiologic reserve and increased vulnerability to stressors, leading to adverse outcomes. We and others have identified that chronic inflammation and immune activation play an important role in aging and frailty, but the etiology of chronic inflammation and immune activation in aging HIV+ and HIV- populations remains obscure. Chronic CMV infection, which is highly prevalent in both the geriatric population and HIV+ persons and causes a very large expansion of T-cells, has long been thought to contribute to shrinking of the T cell repertoire and chronic inflammation and immune activation. We have published that: 1) presence of CMV viral DNA in peripheral monocytes, which is detected in about 60% of CMV-seropositive elderly persons, is strongly correlated with frequency of CMV pp65-specific CD8+ T cells and chronic inflammation (elevated serum neopterin and IL-6 levels); and 2) T-cell responses to CMV are very broad, with responses to CMV pp65 or IE1 (the two most studied CMV antigens) constituting only <12% of the total CD4+ and <40% of the total CD8+ CMV-directed T- cell responses measured using overlapping peptides covering 19 CMV open reading frames (ORFs). Moreover, our published pilot data in men who have sex with men (MSM) in the Multicenter AIDS Cohort Study (MACS) indicate that the total IL-2 response of CD4 T cells to these CMV ORFs (but not to only pp65 and IE1) is strongly correlated with markers of chronic inflammation and immune activation and predicts onset of frailty. While these pilot findings could have broad implications, the precision of the estimated correlations is limited by the small sample size studied to date. Thus, this R21 is designed to confirm, and improve the precision of, these observations in a larger sample of MACS men, both HIV- and HIV+. Our specific aims are to: 1) test the hypothesis that the magnitude of the total CMV-specific T-cell response is strongly correlated with the level of chronic inflammation and immune activation in frail and nonfrail HIV- and virologically suppressed HIV+ men; and 2) explore whether the magnitude of the total CMV-specific T-cell response predicts incident frailty in nonfrail HIV- and HIV+ men. The data obtained will provide needed insight into the impact of chronic CMV infection on chronic inflammation and immune activation, and onset of frailty, in aging HIV+ and HIV- MSM. The data obtained will provide an important foundation for future studies to a) determine if chronic CMV infection is correlated with chronic inflammation and immune activation in HIV- and HIV+ women and non-MSM men; b) clarify the biologic basis of CMV-induced inflammation and immune activation; and, c) if appropriate, design clinical trials of anti- CMV and/or anti-inflammatory therapy for prevention of age-related conditions (e.g., frailty) in aging HIV- and HIV+ individuals.